Does Zonal Aganglionosis Really Exist? Report of a Rare Variety of Hirschsprung's Disease and Review of the Literature

The aganglionic segment of intestine in Hirschsprung's disease begins at the anus and extends proximally for a distance that varies from case to case. Occasional reports describe patients in whom the aganglionosis is segmental, with normal distal innervation or a skip area of normal innervation within an area of aganglionosis. This paper describes 4 patients with Hirschsprung's disease wherein a segment of normally innervated colon was found in an otherwise aganglionic colon. Two of these patients were siblings with different fathers. Problems encountered in the management of these patients are detailed. In a critical review of the literature, 2 additional male patients with well-documented zonal aganglionosis were identified.

Although variations from the usual morphology or Hirschsprung's disease do exist, they are so rare that they merit clinical consideration only when the anatomic record and the clinical course are in obvious disagreement. Rectal biopsy remains the best method for the diagnosis of Hirschsprung's disease.     

Zonal colonic aganglionosis

The customary approach to the diagnosis of Hirschsprung's disease is based on the existence of a single distal aganglionic region extending to the anal margin. Segmental aganglionosis, however, may involve only a limited segment of colon which is interposed between lengths of normal bowel. Awareness of this variant aids in the interpretation of the barium enema in children with signs and symptoms of aganglionosis, especially when the rectal biopsy is normal.     

Selective chemical ablation of the enteric plexus in mice

 Although genetically aganglionic mice such as piebald lethal and lethal spotted mice exhibit striking similarities to the human condition of Hirschsprung's disease (HD), the aganglionic segment is very short and always located in the distal part of the rectum. Topical application of benzalkonium chloride (BAC) to the rectum of rats has been reported to result in segmental aganglionosis. To induce chemical ablation of the enteric plexus in mice to produce an aperistaltic narrow segment simulating HD, 32 mice were divided into three groups: (1) abdominal (n=12), for sigmoid colon treatment; (2) rectal (n=10), for rectum treatment; and (3) controls (n=10). For groups 1 and 2, 0.1% BAC was applied to a 1-cm serosal surface of the bowel for 15 min. In the controls, isotonic saline was applied in this fashion. A detailed histologic examination was performed using hematoxylin and eosin staining and acetylcholinesterase histochemistry. Ten animals (9 in group 1 and 1 in group 2) died 1 to 9 weeks after BAC treatment. Autopsy revealed a narrow segment of bowel at the site of BAC treatment and marked dilatation of the bowel proximal to the narrow segment. The remaining animals were killed 12 weeks after BAC treatment. Histologic examination demonstrated normal myenteric and submucous plexuses in the controls, whereas there was a total lack of innervation in the BAC-treated segments. Topical application of BAC thus successfully produced a narrow aganglionic segment of bowel in normal mice. This model provides the basis for future studies to investigate the pathophysiology of HD and megacolon and for comparison with genetically aganglionic mice. Accepted: 18 April 2001     

Intestinal aganglionosis: a histologic and acetylcholinesterase histochemical study

Varying results have been reported with the use of acetylcholinesterase (AchE) staining to diagnose Hirschsprung's disease in rectal suction biopsy. We analyzed the histology and AchE staining of rectal biopsies from 10 patients with documented intestinal aganglionosis and 57 patients with ganglionic bowel. The results show that histologic identification of submucosal ganglion cells is reliable in excluding Hirschsprung's disease and that the absence of ganglion cells in an adequate suction biopsy is highly suggestive of intestinal aganglionosis. Four AchE staining patterns were recognized; the staining patterns overlap in some patients who have and some who lack ganglion cells. The AchE staining pattern did not correlate with sex or age of the patients, or with the length of the aganglionic segment. The acetylcholinesterase stain is not a reliable method of making or excluding a diagnosis of intestinal aganglionosis except when AchE-positive fibers are increased in both the lamina propria and muscularis mucosae. This AchE staining pattern occurred in 6 of our 10 patients with Hirschsprung's disease. In addition, eight segments of aganglionic colon were studied that included 2 cases of total colonic aganglionosis in which hypertrophic, AchE-positive nerve fibers were absent in all layers of bowel wall. This last finding suggests that an abnormality in the preganglionic cholinergic fiber or extrinsic neuron is involved in the pathogenesis of this unusual form of total colonic aganglionosis.     

Symptoms,diagnosis, and therapy of neuronal intestinal dysplasia masked by Hirschsprung's disease

Twenty-four cases of concomitant Hirschsprung's disease (HD) and neuronal intestinal dysplasia (NID) are presented. The clinical picture is characterized by the early and acute onset of HD symptoms. The diagnosis is established by means of rectal and colonic biopsies. Open biopsies during laparotomy should be taken without injury to the mucosa. Early surgical therapy consists of extended resection of the aganglionic segment and the colon affected by NID up to the splenic flexure. Complications are imminent if the aganglionosis masks the symptoms of NID and, accordingly, only the aganglionic segment is resected. As an alternative, postponed resection of the aganglionic segment alone is proposed once the NID-affected bowel develops functional maturation. In children who do not show an improvement of colon dysmotility, however, extended resection is recommended at the age of 4 years. In follow-up studies of colon motility, functional colon sonography is used.Offprint requests to:} G. Pistor     

The distributions and coexistence of peptides in nerve fibres of large bowel affected by Hirschsprung's disease

The distributions of nerve fibres immunoreactive for the peptides calcitonin gene-related peptide (CGRP), enkephalin (ENK), neuropeptide Y (NPY), somatostatin (SOM), substance P (SP), and vasoactive intestinal peptide (VIP) and the catecholamine-synthesizing enzyme tyrosine hydroxylase (TH) were studied in healthy colon and samples of ganglionic and aganglionic colon from cases of proven Hirschsprung's disease. Studies of coexistence of reactivities in nerve fibres were performed to predict the possible origins of fibres that are found in the aganglionic bowel, e. g., from sensory or sympathetic ganglia. The muscularis externa of the ganglionic colon contained many nerve fibres immunoreactive for ENK, SP, and VIP, fewer for NPY, and only rare fibres reactive for CGRP, SOM, or TH. In ganglionic colon reactivities for SP and ENK coexisted in nerve fibres in the muscularis externa but in aganglionic colon no ENK immunoreactivity was found and most SP fibres were double-labelled with CGRP reactivity, indicating their probable sensory nature. Abnormally increased numbers of somatostatin-reactive fibres and noradrenergic fibres (marked by TH) were noted in the external muscle, but no coexistence was seen between these reactivities and only a small proportion of the noradrenergic fibres in the muscle showed NPY reactivity although almost all around blood vessels did. Many fibres in the diseased segment had coexistence of NPY and VIP reactivities; these may arise from more orally located intrinsic cell bodies or from pelvic parasympathetic ganglia. In the mucosa of aganglionic colon there was a striking lack of SP-reactive fibres while other fibre types were often normal in number. It is concluded that nerve fibres from sensory ganglia, sympathetic ganglia, nerve cells located more oral in the ganglionated part, and possibly from pelvic parasympathetic ganglia invade the aganglionic bowel in Hirschsprung's disease.     

The epidemiology and enzyme histotopochemical characterization of ultrashort-segment Hirschsprung's disease

The enzyme histotopochemical characteristics of ultrashort segment Hirschsprung's disease are described on the basis of 18 cases of this form of impaired motility of the distal rectum, as diagnosed by biopsy in the last 20 years. Unfixed specimens of the rectal segment involved show significantly increased acetylcholinesterase activity in the parasympathetic fibers of the muscularis mucosae alone, the similar change in the lamina propria mucosae characteristic of classical Hirschsprung's disease usually being absent. In strip biopsy specimens of the rectal mucosa taken at the pectinate line, a transition is sometimes observed from aganglionic to normal innervation. The diagnosis of ultrashort segment Hirschsprung's disease may thus be missed if biopsies are taken too high, and it is therefore advisable to take the first biopsy at the pectinate line and further biopsies 1, 2, and 4 cm proximal to it or, alternatively, to take a strip biopsy. Two-thirds of the patients in this series were under 1 year of age at diagnosis, with the remainder between 4 and 21 years. Overall, ultrashort segment Hirschsprung's disease accounted for about 10% of all the cases of aganglionosis of the rectum and rectosigmoid (Hirschsprung's disease) encountered. However, improved knowledge of this particular form of the disease meant that the rate of diagnosis was considerably higher in the second half of the period, at 14% of all cases of aganglionosis and 6.8% of all cases of congenital innervation failures of the gut. The disease is thus relatively rare, though more common than total aganglionosis of the colon (Zuelzer-Wilson syndrome). The sex ratio — five males to one female — is similar to that for classical Hirschsprung's disease. Enzyme histotopochemical staining for acetylcholinesterase activity in the parasympathetic fibers of the rectal mucosa has confirmed beyond all doubt that ultrashort segment Hirschsprung's disease does exist as a special form of aganglionosis of the distal rectum.In honour of Professor Dr. Ruth Silberberg (Jerusalem), on her 80th birthday. Offprint requests to: W. Meier-Ruge at the above address     

Laparoscopic-assisted approaches for the definitive surgery for Hirschsprung's disease

The surgical management of Hirschsprung's disease has progressed from a two- or three-stage procedure to a primary operation over the last 25 years. More recently, definitive surgery for Hirschsprung's disease has been performed using minimally invasive techniques. The Swenson, Duhamel and Soave endorectal pull-through procedures have all been reported using minimally invasive approaches. The endorectal dissection has become the dominant minimal access procedure because of the ease and reliability in performing this technique and the excellent results obtained. Although a transanal endorectal pull-through can be performed without laparoscopy, the laparoscopic-assisted transanal endorectal pull-through is a much more versatile technique and allows early biopsies to determine the extent of aganglionic and dysfunctional bowel before ablation of the rectum and mesocolon. The authors use a laparoscopic-assisted transanal pull-through for aganglionosis of the left and transverse colon. Total colon aganglionosis or aganglionosis of the ascending colon is managed by a laparoscopic-assisted Duhamel procedure which provides a better reservoir in patients with a short or absent colon.     

先天性巨结肠RET基因转录水平的研究

目的 探讨ＲＥＴ基因的表达情况与先天性巨结肠发生的关系。方法 采用ＲＴ－ＰＣＲ技术对１２例先天性巨结肠的狭窄段,移行段及扩张段分别做ＲＥＴ基因的表达,并以Ｇ３ＰＤＨ作内参标,观察ＲＥＴ基因的表达情况。结果 发现ＲＥＴ基因的表达从扩张段→移行段→狭窄段是逐渐减低的。结论 提示ＲＥＴ基因与先天性巨结肠的发生有一定的关系。     

Ultrastructural demonstration of abnormal multiaxonal Schwann-cell units in Hirschsprung's disease

The pathophysiology of Hirschsprung's disease is not fully understood. Using light microscopy we have previously demonstrated the absence of a unique Schwann-cell antigen in the circular muscle of aganglionic colon identified by D₇ monoclonal antibody. In an attempt to characterise the morphological changes in neuronal cells at subcellular level, we studied innervation patterns in normal and aganglionic colon by electron microscopy. The most striking observation on ultrastructural serial examination of the entire resected specimen of colon from patients with Hirschsprung's disease was the presence of grossly swollen monoaxonal or oligoaxonal Schwann cell units with loss of cellular contents in the circular muscle of aganglionic colon. The extent of subcellular changes in Schwann cells and axons corresponded with a diminution of immunoreactivity with a panel of neuronal cell antibodies. These ultrastructural findings suggest that degenerative changes in Schwann cells and axons within the circular muscle coat of aganglionic segment may be a significant factor in the pathogenesis of Hirschsprung's disease. Offprint requests to: P. Puri     

先天性巨结肠Cajal间质细胞的研究

目的　本研究通过观察Cajal间质细胞 (interstitialcellofCajal,ICC)在先天性巨结肠患者狭窄段、移行段、扩张段中的分布情况 ,探讨ICC在先天性巨结肠发病中的作用。方法　收集我院1999～ 2 0 0 2年 2 6例先天性巨结肠患儿标本。短段型 2 4例 ,长段型 2例。于手术中分别选取扩张段 ,移行段及狭窄段肠壁的全层组织。采用SP法 (过氧化物酶标记的链霉卵白素法 )免疫组织化学技术 ,对 2 6例先天性巨结肠的狭窄段、移行段及扩张段标本分别进行c kit免疫组织化学反应 ,观察Ca jal间质细胞分布情况。 结果　发现ICC的密度从扩张段→移行段→狭窄段是逐渐减低的。ICC与肌间神经丛关系密切 ,在扩张段ICC分布在神经丛的周边部和内部 ,且数量相对较多 ,在狭窄段ICC偶见于神经丛的周边部 ,在神经丛内部未见该细胞。光学显微镜下比较同一例患者扩张段和狭窄段神经丛中Cajal间质细胞的数目不同 (t=2 3.0 4 ,P <0 .0 5 ) ,有统计学显著性差异。结论　ICC的分布异常与先天性巨结肠的发生有密切关系。我们推测胚胎基质的某种缺陷不仅损害了神经嵴细胞的移行 ,也影响ICC的分化和成熟。我们可以推论 ,与HD肠壁神经节缺失一样 ,ICC分布异常导致HD病变肠管慢波节律和兴奋传导异常 ,从而引起或加重HD的发病。     

TOTAL AGANGLIONOSIS OF THE COLON (HIRSCHSPRUNG'S DISEASE) and CONGENITAL FAILURE OF AUTOMATIC CONTROL OF VENTILATION (ONDINE'S CURSE)

Abstract. Stern, M., Hellwege, H. H., Grävinghoff, L. and Lambrecht, W. (Department of Paediatrics and Department of Surgery, University Hospital Eppendorf, Hamburg, Federal Republic of Germany). Total aganglionosis of the colon (Hirschsprung's disease) and congenital failure of automatic control of ventilation (Ondine's curse). Acta Paediatr Scand, 70:121, 1981.–Total aganglionosis of the colon presenting with small intestinal obstruction in the neonatal period was observed in combination with congenital alveolar hypoventilation requiring continuous mechanical ventilation in a boy. The patient died aged 15 months from acute dehydration due to enteritis, long after total resection of the aganglionic bowel had been performed. Pulmonary hypertension was found in the newborn period. There was progressive right ventricular myocardial hypertrophy. This is the fourth case reported with a combination of defects involving nerve cell function of the brain stem and gastrointestinal tract.     

Clinical evaluation of diagnostic methods for Hirschsprung's disease

The results of a comparative study of diagnostic methods for Hirschsprung's disease are reported. Since December 1979, the authors have studied four new methods. First, anorectal manometry, a simple, safe, and atraumatic method with a high diagnostic success rate of over 92.6%. Patients with Hirschsprung's disease have no relaxation reflex. By using manometry, one may differentiate idiopathic megacolon from ultrashort segment aganglionosis, but there is a high false-negative rate (63.3%) in normal newborns. Second, rectal mucosal acetylcholinesterase (AChE) histochemistry had a high success rate of 96.6% in 58 cases of Hirschsprung's disease. Two cases showed false-negative results that seemed to be related to incorrect manipulation. In 6 cases of neonatal Hirschsprung's disease, the success rate was 100%. Third, erythrocyte AChE activity was assessed in 59 newborns and children with Hirschsprung's disease; in 45, this activity was 92.11 ± 9.66 U/ml, which was higher than that of 127 normal controls (P < 0.001). The erythrocyte AChE activity of 14 neonates with Hirschsprung's disease was 73.31 ± 8.82 U/ml, higher than that of 32 normal controls (50.32 ± 8.54 U/ml, P < 0.0001). The results showed that erythrocyte AChE activity was proportional to the length of aganglionic bowel and its activity was prone to decrease after resection of the abnormal segment. The erythrocyte AChE assay may be used as an initial screening test in cases of suspected Hirschsprung's disease. Fourth, have not yet had enough experience with electromyography to evaluate it.The authors believe that by combining these different methods, a correct diagnosis of Hirschsprung's disease can be made without a full-thickness biopsy, even in atypical and difficult cases. Offprint requests to: She Yaxiong, at the above address     

Total colonic aganglionosis: a case study

Total colonic aganglionosis (TCA) is a rare, hybrid form of Hirschsprung's disease. It is a functional rather than mechanical obstruction, characterized by the absence of intrinsic ganglion cells in the myenteric and submucosal plexuses of the bowel wall. Ganglion cells regulate normal colonic peristaltic activity. Paucity of ganglion cells results in an aganglionic segment of bowel that is functionally abnormal and does not propagate the normal peristaltic wave that moves to it from the proximal ganglionic bowel. The lesion originates in the rectum and extends proximally over a variable distance of the bowel. The further the lesion extends, the more difficult the management becomes. Clinical and radiologic findings can be useful in diagnosis, but they are not pathognomonic. The definitive diagnosis is made following suction biopsy of the rectum, colon, and ileum. Ultimate treatment for TCA is surgical, although no single surgical procedure has been proven superior. Total parenteral nutrition during the postoperative period is essential to ensure appropriate fluid and electrolyte status. Improvements in supportive care and earlier recognition and diagnosis of TCA in infants have led to a significantly increased rate of survival since the lesion was first recognized. The embryology, pathogenesis, clinical presentation, diagnosis, management prognosis, and outcome of TCA are discussed. A case study is presented.     

Late study results following megacolon operations

The basic pathophysiologic disturbance in Hirschsprung's disease is a functional obstruction caused by defective intramural nerve supply and by internal anal sphincter achalasia. Therapy consists in resecting the dysganglionic bowel segment. In each case however an aganglionic segment of different length and an internal analsphincter with a different degree of achalasia remain in situ. Therefore the postoperative results are dependant on an equilibrium between the proximal normal innervated colon and the length and function of the remaining aganglionic and achalic parts of the rectum and anal canal. In about one third of all patients with Hirschsprung's disease disturbances of this equilibrium postoperatively lead to enterocolitis, encopresis, or chronic constipation. Five years later however the authors could observe enterocolitis in only 7.3% chronic constipation in 9.5% and encopresis in 13.9% of their operated patients. With increasing time after operation there is a growing tendency towards the spontaneous regeneration. Therefore, the prognosis of Hirschsprung's disease is very good: about 90% of all cases can be cured.     

Achalasia of the anal sphincter

Enzyme-histotopochemical studies of parasympathetic innervation in the internal anal sphincter muscle of 73 children with anal sphincter achalasia indicated that in Hirschsprung's disease and type B neuronal intestinal dysplasia (NID) the internal sphincter displays a pattern of changes analogous to that seen in the wall of the rectum. In Hirschsprung's disease the internal sphincter is also aganglionic, and its parasympathetic fibres exhibit increased acetylcholinesterase (ACE) activity in NID there is moderately increased ACE activity, with ganglionic neurons embedded singly or in groups in the thick afferent parasympathetic fibers. The innervation defect may be confined to the sphincter, or aganglionosis of the sphincter may be associated with proximal NID. Offprint requests to: J. Welskop     

Histopathological differences between recto-sigmoid Hirschsprung's disease and total colonic aganglionosis

Total colonic aganglionosis (TCA) is a severe form of ultra long Hirschsprung's disease with an incidence of 2 to 14% among all forms of intestinal aganglionosis. C-kit positive interstitial cells of Cajal (ICCs) are pacemaker cells that play a key role in the motility function of the bowel. The aim of this study was to compare the innervation and ICCs distribution in total colonic and recto-sigmoid HD. Full thickness colonic specimens were obtained from four children with TCA, ten with recto-sigmoid HD and four controls. Single immunohistochemistry using peripherin, neuronal nitric oxide synthase (nNOS) and c-kit antibody was performed and analysed in light microscopy. Additionally, whole-mount preparations were stained using anti c-kit immunohistochemistry and NADPH-diaphorase. In the ganglionic bowel of TCA, recto-sigmoid HD and control patients there was a strong nNOS and peripherin immunoreactivity (IR) in ganglia of myenteric and submucous plexus and in thin nerve fibres in the muscle layers. In the TCA there was weak or lack of nNOS IR in the sparse, short nerve trunks of the myenteric and submucous plexuses and muscle layers, whereas nNOS weakly positive nerve trunks were observed in the recto-sigmoid HD bowel. Peripherin IR was markedly reduced in the TCA specimens compared to recto-sigmoid HD. In the TCA specimens there was a lack of ICCs-MY in the smooth muscle layer in all the specimens, whereas in the recto-sigmoid aganglionic bowel ICCs-MY were markedly reduced. Whole-mount preparations showed lack of ICCs-MY and a markedly reduced number of NADPH-positive nerve trunks in TCA. Our findings demonstrate clear histopathological differences between rectosigmoid Hirschsprung's disease and total colonic aganglionosis.     

Whole-mount NADPH-diaphorase histochemistry is a reliable technique for the intraoperative evaluation of extent of aganglionosis

Multiple seromuscular biopsies at three levels (narrow segment, transitional zone, and dilated segment) were taken and investigated intraoperatively to determine the extent of aganglionosis. Using the whole-mount preparation technique, circular muscle fibers were separated from the specimens. After a short prefixation, the muscle fibers were stained by the NADPH-diaphorase technique and were examined within 20–25 min. A fine and dense neuronal meshwork was observed between circular muscle fibers in the normal and ganglionic part of the bowel. In contrast, there was a complete lack of NADPH-diaphorase-positive fibers in the circular muscle of aganglionic colon. In the transitional zone, NADPH-diaphorase-positive fibers were markedly reduced compared to the ganglionic region. The density of these fibers increased and attained normal levels in the proximal bowel above the transition zone. These results suggest that whole-mount NADPH-diaphorase histochemistry is a three-dimensional technique suitable for the intraoperative evaluation of extend of aganglionosis. The technique is sufficiently rapid to be used in conjunction with routine frozen sections to assist in the diagnosis and in selecting the optimal level of resection at the time of pull-through operation.     

Abnormal expression of blood group-associated antigen (BGA) in colon of Hirschsprung's disease

The entire segment of resected colon obtained from 15 patients with Hirschsprung's disease (HD) was examined with conventional mucin histochemistry (PASAB, HID-AB) to investigate the mucin composition and blood group-associated antigens (BGA) (sialosyl-Le^a, Le^a, Le^y, Le^b) for detecting mucosal cell differentiation. The BGA Le^b were absent in normal distal colon and rectum but present in fetal colon. Immunoreactivity of Le^b, which is a marker of undifferentiated crypt cells, was observed through out the crypts in aganglionic colon. Depletion of sulphated and neutral mucin was also a characteristic finding in the aganglionic mucosa. These findings suggest that the colonic mucosa of aganglionic bowel represents persistence of a fetal stage of development. These cellular abnormalities may be a factor in the pathogenesis of enterocolitis complicating HD.     

Total intestinal aganglionosis with involvement of the stomach

Total intestinal aganglionosis is the rarest form of Hirschsprung's disease, with absence of ganglia from the duodenum to the rectum. In addition to those cases reported in the literature, a neonate with total intestinal aganglionosis with involvement of the stomach is presented. Diagnosis of this extensive form of Hirschsprung's disease is a major problem. These patients lie beyond the scope of present surgical expertise, and the outcome is universally fatal.